In vitro study for clotting function aid activation mechanism in the gene therapy for haemophilia A
| Project/Area Number |
14570761
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Nara Medical University |
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Principal Investigator |
SHIMA Midori Nara Medical University, Pediatrics, Associate Professor, 医学部・小児科, 助教授 (30162663)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Ichiro Nara Medical University, Pediatrics, Lecturer, 医学部・小児科, 講師 (00201616)
SAKURAI Yoshihiko Nara Medical University, Pediatrics, Lecturer, 医学部・小児科, 助手 (80347559)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Clot waveform / factor VIII / hemophilia / 血友病A / トロンビン生成 / 遺伝子治療 |
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| Research Abstract |
1.Clot waveform analysis : For the purpose of monitoring the very low level of factor VIII activity expressed during the gene therapy for hemophilia A, we performed apt-based clot waveform analysis by real time-monitored transmittance of clotting process and measured the clotting time, clotting velocity, maximum clotting velocity, clotting acceleration and its maximum acceleration. We found that the clot waveform parameters such as clotting time, maximum clotting velocity and maximum clot acceleration correlates well with the very low level of factor VIII activity with range of 0.2-1.0 IU/dl. This result indicated that the presence and significance of factor VIII less than 1.0 IU/dl. Furthermore the results also indicated that the measurement of lsuch low level of factor VIII activity is possible. We measured for the presence of low level of factor VIII activity in hemophilia A patients diagnosed as severe type by conventional clotting assay. We found that severe hemophilia A patients
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with low level of factor VIII less than 1.0 IU/dl. No factor VIII activity was detected in patients with intron 22 -related inversion.
2.Factor VIII activation and inactivation mechanism : Factor VIII acts as cofactor in factor X activating reaction due to activated factor IX. Factor VIII itself can be activated by thrombin and inactivated by activated protein C. We found that synthetic peptide corresponding to the factor Xa binding region of factor VIII inhibited intrinsic pathway coagulation. Therefore these results indicated that the factor Xa-catalyzed FVIII activation is essential in the clotting function. Factor VIII inactivation due to activated protein C is known to be protected by von Willebrand factor. We found that the activated protein C compete with von Willebrand factor in binding to factor VIII. These suggested that the factor VIII inactivation by activated protein C is regulated by von Willebrand factor and the binding site for activated protein C locates in close to von Willebrand binding site. Less
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Report
(4 results)
Research Products
(29 results)
